DESCRIPTION: Abstract Cervical spinal cord injury (C-SCI) is a common and frequently devastating battlefield injury that can result in a broad range of life-long locomotor, spasticity, and pain disabilities. Although SCI involves a cascade of numerous pathophysiological events that evolve over time, research aimed at therapy development has almost exclusively focused on single therapies which have failed in multicenter clinical trials to decrease physical assistance required for locomotion. Positive therapeutic benefits have been reported for locomotor therapy and, independently, for therapy utilizing transcranial magnetic stimulation (TMS) to reduce disability in a variety of neurologic conditions. The proposed studies are designed to test the potential for the combination of locomotor training and TMS to produce convergent amplification of endogenous neuroplastic and repair mechanisms to significantly enhance locomotor recovery, and reduce spasticity, gait and pain disability. Spasticity is one of the more common complications of SCI for which new therapeutic avenues are continually being pursued. Multidisciplinary studies will quantitate therapeutic impact on disability, changes in underlying mechanisms, and provide comprehensive neurological and physiological safety assessments at acute and chronic therapeutic windows using a range of doses and combinations. Three complementary specific aims are proposed that are based upon supporting preliminary data and which will employ a battery of state of the art multi-organ systems monitoring, behavioral, neurophysiological, immunohistochemical (IHC), and molecular-based techniques that have been extensively employed in this laboratory. In this proposal we aim to: 1) compare the efficacy and safety of single pulse TMS of the spinal cord (SC) (TMSsc), and treadmill locomotor training (Tm), tested alone and in combination in acute C-SCI on the excitability of stretch reflexes, gait kinematics, pain sensitivity, and selected measures of physiological safety, 2) compare the efficacy of TMSsc and Tm locomotor training, tested alone and in combination in chronic C-SCI on spasticity, on gait kinematics and pain sensitivity, 3) identify key neurobiological processes (particularly, therapy induced up-regulation of specific signaling mechanisms) correlated with changes induced by injury and treatment in regard to spasticity, gait, and pain. Immunohistochemical (IHC) and molecular expression of three factors that are essential for normal pattern of presynaptic and postsynaptic inhibition: GABA/GABAb receptors and descending noradrenergic (NE) fiber projection. In addition, specific molecular markers for pain (GCH1, GTP cyclohydrolase 1; SP, Substance P; CGRP, calcitonin gene-related peptide, a marker for pain and sprouting of SC afferents; Isolectin B4, IB4, marker for microglia) will be tested. Hypothesis: We propose that therapy induced normalization of spasticity measures will in part, be mediated by increased rate-dependent inhibition in the SC circuits, and these neurophysiological measures will correlate with significant up-regulation of immuno-expression of GABA/GABAb receptors and NE. We propose that therapy induced normalization of outcome measures for pain will correlate with reduced immune-expression of pain markers GCH1, SP, CGRP, and IB4. Translation of these findings and the demonstration of benefit from locomotor and TMSsc therapies could lead to more specific and potentially more effective locomotor therapy clinical trials in combat C-SCI patients which ultimately benefit the veterans' health care system.